The ability of baroreflex activation to improve blood pressure and resistance vessel function in spontaneously hypertensive rats is dependent on stimulation parameters.

Baroreflex activation by electric stimulation of the carotid sinus (CS) effectively lowers blood pressure. However, the degree to which differences between stimulation protocols impinge on cardiovascular outcomes has not been defined. To address this, we examined the effects of short- and long-duration (SD and LD) CS stimulation on hemodynamic and vascular function in spontaneously hypertensive rats (SHRs). We fit animals with miniature electrical stimulators coupled to electrodes positioned around the left CS nerve that delivered intermittent 5/25 s ON/OFF (SD) or 20/20 s ON/OFF (LD) square pulses (1 ms, 3 V, 30 Hz) continuously applied for 48 h in conscious animals. A sham-operated control group was also studied. We measured mean arterial pressure (MAP), systolic blood pressure variability (SBPV), heart rate (HR), and heart rate variability (HRV) for 60 min before stimulation, 24 h into the protocol, and 60 min after stimulation had stopped. SD stimulation reversibly lowered MAP and HR during stimulation. LD stimulation evoked a decrease in MAP that was sustained even after stimulation was stopped. Neither SD nor LD had any effect on SBPV or HRV when recorded after stimulation, indicating no adaptation in autonomic activity. Both the contractile response to phenylephrine and the relaxation response to acetylcholine were increased in mesenteric resistance vessels isolated from LD-stimulated rats only. In conclusion, the ability of baroreflex activation to modulate hemodynamics and induce lasting vascular adaptation is critically dependent on the electrical parameters and duration of CS stimulation.

Electrical stimulation of the carotid sinus lowers arterial pressure and improves heart rate variability in L-NAME hypertensive conscious rats.

We evaluated the effects of long-term (48 h) electrical stimulation of the carotid sinus (CS) in hypertensive rats. L-NAME-treated (10 days) Wistar rats were implanted with a catheter in the femoral artery and a miniaturized electrical stimulator attached to electrodes positioned around the left CS, encompassing the CS nerve. One day after implantation, arterial pressure (AP) was directly recorded in conscious animals for 60 min. Square pulses (1 ms, 3 V, 30 Hz) were applied intermittently (20/20 s ON/OFF) to the CS for 48 h. After the end of stimulation, AP was recorded again. Nonstimulated rats (control group) and rats without electrodes around the CS (sham-operated) were also studied. Next, the animals were decapitated, and segments of mesenteric resistance arteries were removed to study vascular function. After the stimulation period, AP was 16 ± 5 mmHg lower in the stimulated group, whereas sham-operated and control rats showed similar AP between the first and second recording periods. Heart rate variability (HRV) evaluated using time and frequency domain tools and a nonlinear approach (symbolic analysis) suggested that hypertensive rats with electrodes around the CS, stimulated or not, exhibited a shift in cardiac sympathovagal balance towards parasympathetic tone. The relaxation response to acetylcholine in endothelium-intact mesenteric arteries was enhanced in rats that underwent CS stimulation for 48 h. In conclusion, long-term CS stimulation is effective in reducing AP levels, improving HRV and increasing mesenteric vascular relaxation in L-NAME hypertensive rats. Moreover, only the presence of electrodes around the CS is effective in eliciting changes in HRV similar to those observed in stimulated rats.

Carotid sinus nerve electrical stimulation in conscious rats attenuates systemic inflammation via chemoreceptor activation.

Recent studies demonstrated a critical functional connection between the autonomic (sympathetic and parasympathetic) nervous and the immune systems. The carotid sinus nerve (CSN) conveys electrical signals from the chemoreceptors of the carotid bifurcation to the central nervous system where the stimuli are processed to activate sympathetic and parasympathetic efferent signals. Here, we reported that chemoreflex activation via electrical CSN stimulation, in conscious rats, controls the innate immune response to lipopolysaccharide attenuating the plasma levels of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). By contrast, the chemoreflex stimulation increases the plasma levels of anti-inflammatory cytokine interleukin 10 (IL-10). This chemoreflex anti-inflammatory network was abrogated by carotid chemoreceptor denervation and by pharmacological blockade of either sympathetic - propranolol - or parasympathetic - methylatropine - signals. The chemoreflex stimulation as well as the surgical and pharmacological procedures were confirmed by real-time recording of hemodynamic parameters [pulsatile arterial pressure (PAP) and heart rate (HR)]. These results reveal, in conscious animals, a novel mechanism of neuromodulation mediated by the carotid chemoreceptors and involving both the sympathetic and parasympathetic systems.

Cholinergic stimulation with pyridostigmine protects myocardial infarcted rats against ischemic-induced arrhythmias and preserves connexin43 protein.

We investigated the effects of acute pyridostigmine (PYR) treatment, an acetylcholinesterase inhibitor, on arterial pressure (AP), heart rate (HR), cardiac sympathovagal balance, and the incidence of arrhythmias during the first 4 h after myocardial infarction (MI) in anesthetized rats. Male Wistar rats were implanted with catheters into the femoral artery and vein for AP recordings and drug administration. Rats received the autonomic receptor blockers methyl-atropine (1 mg/kg iv) and propranolol (2 mg/kg iv) at intervals of 15 min, 1 h after saline (n=16) or PYR (0.25 mg/kg iv, n=18), to indirectly assess sympathovagal balance. Acute treatment with PYR increased cardiac vagal (86±7 vs. 44±5 beats/min) and decreased sympathetic tone (-31±8 vs. -69±7 beats/min). Different animals were implanted with ECG electrodes and catheters. A large MI was induced via left coronary artery ligation after basal recordings. Rats received PYR (n=14) or saline (n=14) 10-15 min after MI, and the recordings lasted up to 4 h. In part of the animals, hearts were removed for connexin43 quantification after all procedures. MI elicited a fall in AP (-45±5 mmHg), a progressive rise in HR (26±14 beats/min), and an increase in corrected QT interval (33±13 ms). PYR elicited a prompt bradycardia (-50±14 beats/min) that returned to basal levels over time, and it prevented the lengthening of the corrected QT interval. Treatment with PYR increased by ∼20% the occurrence of rats free of arrhythmias after MI. MI markedly decreased connexin43 in left ventricles, and PYR treatment partially prevented this decrease.